Method of treating depression, mood disorders and anxiety disorders using neuromodulation

ABSTRACT

The present application involves a method and a system for using electrical stimulation and/or chemical stimulation to treat depression. More particularly, the method comprises surgically implanting an electrical stimulation lead and/or catheter that is in communication with a predetermined site which is coupled to a signal generator and/or infusion pump that release either an electrical signal and/or a pharmaceutical resulting in stimulation of the predetermined site thereby treating the mood and/or anxiety.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent Ser. No. 13/913,189,filed Jun. 7, 2013 which is a continuation of Ser. No. 13/478,646, filedMay 23, 2012 (now U.S. Pat. No. 8,467,878) which is a continuation ofU.S. application Ser. No. 12/686,030, filed Jan. 12, 2010, now U.S. Pat.No. 8,190,264, which is a continuation of U.S. application Ser. No.11/469,669, filed Sep. 1, 2006, now U.S. Pat. No. 7,653,433, which is acontinuation of application Ser. No. 10/872,277, filed Jun. 18, 2004,now U.S. Pat. No. 7,346,395, which claims the benefit of U.S.Provisional Application No. 60/511,268, filed Oct. 15, 2003, U.S.Provisional Application No. 60/550,164, filed Mar. 4, 2004, and CanadianApplication No. 2,432,810 filed Jun. 19, 2003, all of which areincorporated herein by reference in their entirety.

TECHNICAL FIELD

This application relates to nervous tissue stimulation for treatingdepression, anxiety disorders and mood disorders, and more particularlyto modulating nervous tissue at a predetermined stimulation site inbrain tissue.

BACKGROUND

Recent estimates indicate that more than 19 million Americans over theage of 18 years experience a depressive illness each year. The AmericanPsychiatric Association recognizes several types of clinical depression,including Mild Depression (Dysthymia), Major Depression, and BipolarDisorder (Manic-Depression). Major Depression is defined by aconstellation of chronic symptoms that include sleep problems, appetiteproblems, anhedonia or lack of energy, feelings of worthlessness orhopelessness, difficulty concentrating, and suicidal thoughts.Approximately 9.2 million Americans suffer from Major Depression, andapproximately 15 percent of all people who suffer from Major Depressiontake their own lives. Bipolar Disorder involves major depressiveepisodes alternating with high-energy periods of rash behavior, poorjudgment, and grand delusions. An estimated one percent of the Americanpopulation experiences Bipolar Disorder annually.

Significant advances in the treatment of depression have been made inthe past decade. Since the introduction of selective serotonin reuptakeinhibitors (SSRIs), i.e., Prozac®, many patients have been effectivelytreated with anti-depressant medication. New medications to treatdepression are introduced almost every year, and research in this areais ongoing. However, an estimated 10 to 30 percent of depressed patientstaking an anti-depressant are partially or totally resistant to thetreatment. Those who suffer from treatment-resistant depression havealmost no alternatives. Thus, there is a need to develop alternativetreatments for these patients.

The use of electrical stimulation for treating neurological disease,including such disorders as movement disorders including Parkinson'sdisease, essential tremor, dystonia, and chronic pain, has been widelydiscussed in the literature. It has been recognized that electricalstimulation holds significant advantages over lesioning since lesioningdestroys the nervous system tissue. In many instances, the preferredeffect is to modulate neuronal activity. Electrical stimulation permitssuch modulation of the target neural structures and, equallyimportantly, does not require the destruction of nervous tissue. Suchelectrical stimulation procedures include electroconvulsive therapy(ECT), repetitive transcranial (rTMS) magnetic stimulation and vagalnerve stimulation (VNS).

Efforts have been made to treat psychiatric disorders withperipheral/cranial nerve stimulation. Recently, partial benefits withvagus nerve stimulation in patients with depression have been describedin U.S. Pat. No. 5,299,569. Another example of electrical stimulation totreat depression is described in U.S. Pat. No. 5,470,846, whichdiscloses the use of transcranial pulsed magnetic fields to treatdepression. Yet further, U.S. Pat. No. 5,263,480 describes thatstimulation of the vagus nerve may control depression and compulsiveeating disorders and U.S. Pat. No. 5,540,734 teaches stimulation of thetrigeminal or glossopharyngeal nerves for psychiatric illness, such asdepression.

Deep brain stimulation (DBS) has been applied to the treatment ofcentral pain syndromes and movement disorders, and it is currently beingexplored as a therapy for epilepsy. For instance, U.S. Pat. No.6,016,449 and U.S. Pat. No. 6,176,242 disclose a system for theelectrical stimulation of areas in the brain for the treatment ofcertain neurological diseases such as epilepsy, migraine headaches andParkinson's disease.

Various electrical stimulation and/or drug infusion devices have beenproposed for treating neurological disorders. Some devices stimulatethrough the skin, such as electrodes placed on the scalp. Other devicesrequire significant surgical procedures for placement of electrodes,catheters, leads, and/or processing units. These devices may alsorequire an external apparatus that needs to be strapped or otherwiseaffixed to the skin.

However, despite the aforesaid available treatments, there are patientswith major depression that remain treatment refractory and chronicallydisabled. For these severely ill and disabled patients, novel therapiesare required.

SUMMARY

The present application relates to electrical and/or chemicalstimulation applied to areas of the brain not considered in the priorart to play a role in depression. In certain embodiments, theapplication uses electrical stimulation and/or chemical stimulation(i.e., one or more pharmaceuticals) to treat depression. In addition toelectrical and/or chemical stimulation, magnetic stimulation can also beused, such as transcranial magnetic stimulation (“TMS”). According toone representative embodiment, the stimulation modulates areas of thebrain that exhibit altered activity in patients relative topsychiatrically normal control subjects, thereby treating or preventingaffective disorders, for example depression and/or anxiety disorders.Such stimulation is likely to be produced by electrical stimulation, anexcitatory neurotransmitter agonist(s) (i.e., norepinephrine), aninhibitory neurotransmitter antagonist(s), and/or a medication thatincreases the level of an excitatory neurotransmitter (i.e., flouxetine(Prozac®), trazodone).

One representative embodiment utilizes neurosurgical intervention tomodulate the pathological activity of a subcallosal area in patientssuffering from depression or other affective disorders. Suchinterventions include, applying electrical stimulation, herein termed“deep brain stimulation” or DBS, as is currently practiced to treat anumber of disorders like Parkinson's disease. Other stimulations caninclude chemical stimulation such as through the use of pharmaceuticalor drug pumps, for example local delivery of neuroactive substances todisrupt or block the pathological activity stemming from or coursingthrough this area. It is envisioned that such stimulation (i.e.,electrical, magnetic and/or chemical) modulates the gray matter andwhite matter tracts in a subcallosal area, as well as the white mattertracts that are associated with the subcallosal area (such as the whitematter tracts that lead to and from the subcallosal area or that areadjacent to the subcallosal area), which in turn modulates the limbicsystem. Still further, other stimulations may comprise magneticstimulation and/or transplantation of cells.

Certain embodiments involve a method that comprises surgicallyimplanting a device or stimulation system in communication with apredetermined site, for example a subcallosal area. The device orstimulation system is operated to stimulate the predetermined sitethereby treating the mood and/or anxiety disorder. The device orstimulation system may include a probe, for example, an electrodeassembly (i.e., electrical stimulation lead), pharmaceutical-deliveryassembly (i.e., catheters) or combinations of these (i.e., a catheterhaving at least one electrical stimulation lead) and/or a signalgenerator or signal source (i.e., electrical signal source, chemicalsignal source (i.e., pharmaceutical delivery pump) or magnetic signalsource). The probe may be coupled to the electrical signal source,pharmaceutical delivery pump, or both which, in turn, is operated tostimulate the predetermined treatment site. Yet further, the probe andthe signal generator or source can be incorporated together, wherein thesignal generator and probe are formed into a unitary or single unit,such unit may comprise, one, two or more electrodes. These devices areknown in the art as microstimulators, for example, Bion™ which ismanufactured by Advanced Bionics Corporation.

It is envisioned that the predetermined site is a subcallosal area. Asubcallosal area includes, but is not limited to subgenual cingulatearea, subcallosal cingulate area, ventral/medial prefrontal cortex area,ventral/medial white matter, Brodmann area 24, Brodmann area 25, and/orBrodmann area 10. More specifically, the predetermined site is asubgenual cingulate area, more preferably Brodmann area 25/Brodmann area24.

Stimulation of a subcallosal area includes stimulation of the graymatter and white matter tracts associated with the subcallosal area thatresults in an alleviation or modulation of the mood and/or anxietydisorder. Associated white matter tracts includes the surrounding oradjacent white matter tracts leading to or from a subcallosal area orwhite matter tracts that are contiguous with the subcallosal area.Modulating the subcallosal area via electrical and/or chemicalstimulation (i.e., pharmaceutical) and/or magnetic stimulation canresult in increasing, decreasing, masking, altering, overriding orrestoring neuronal activity resulting in treatment of the mood and/oranxiety disorder. Yet further, stimulation of a subcallosal area mayresult in modulation of neuronal activity of other areas of the brain,for example, Brodmann area, 24, Brodmann area 25, Brodmann area 10,Brodmann area 9, the hypothalamus and the brain stem.

Another representative embodiment comprises a method of treating themood and/or anxiety disorder comprising the steps of: surgicallyimplanting an electrical stimulation lead having a proximal end and astimulation portion, wherein after implantation the stimulation portionis in communication with a predetermined site; the stimulation lead iscoupled to or in communication with a signal generator; and anelectrical signal is generated using the signal generator to modulatethe predetermined site thereby treating the mood and/or anxietydisorder. The mood disorder is selected from the group consisting ofmajor depressive disorder, bipolar disorder, and dysthymic disorder. Theanxiety disorder is selected from the group consisting of panicdisorder, posttraumatic stress disorder, obsessive-compulsive disorderand phobic disorder.

In further embodiments, the method can comprise the steps of: surgicallyimplanting a catheter having a proximal end coupled to a pump and adischarge portion for infusing a dosage of a pharmaceutical, whereinafter implantation the discharge portion of the catheter is incommunication with the predetermined stimulation site; and operating thepump to discharge the pharmaceutical through the discharge portion ofthe catheter into the stimulation site thereby treating the mood and/oranxiety disorder. The pharmaceutical is selected from the groupconsisting of inhibitory neurotransmitter agonist, an excitatoryneurotransmitter antagonist, an agent that increases the level of aninhibitory neurotransmitter, an agent that decrease the level of anexcitatory neurotransmitter, and a local anesthetic agent. It isenvisioned that chemical stimulation or pharmaceutical infusion can bepreformed independently of electrical stimulation and/or in combinationwith electrical stimulation.

Another representative embodiment is a method of treating a mood and/oranxiety disorder comprising the steps of: surgically implanting anelectrical stimulation lead having a proximal end and a stimulationportion, wherein after implantation the stimulation portion is incommunication with a predetermined site; surgically implanting acatheter having a proximal end coupled to a pump and a discharge portionfor infusing a dosage of a pharmaceutical, wherein after implantationthe discharge portion of the catheter is in communication with apredetermined infusion site; and coupling the proximal end of the leadto a signal generator; generating an electrical signal with the signalgenerator to modulate the predetermined site; and operating the pump todischarge the pharmaceutical through the discharge portion of thecatheter into the infusion site thereby treating the mood and/or anxietydisorder.

Other representative embodiments include a system for treating subjectswith mood and/or anxiety disorders. The therapeutic system comprises anelectrical stimulation lead that is implanted into the subject's brain.The electrical stimulation lead comprises at least one electrode that isin communication with a predetermined site and delivers electricalsignals to the predetermined site in response to received signals; and asignal generator that generates signals for transmission to theelectrodes of the lead resulting in delivery of electrical signals topredetermined site thereby treating the mood and/or anxiety disorder.The electrical stimulation lead may comprise one electrode or aplurality of electrodes in or around the target area. Still further, thesignal generator is implanted in the subject's body.

Another example of a therapeutic system is a catheter having a proximalend coupled to a pump and a discharge portion for infusing a dosage of apharmaceutical, wherein after implantation the discharge portion of thecatheter is in communication with a predetermined stimulation site; anda pump to discharge the pharmaceutical through the discharge portion ofthe catheter into the predetermined stimulation site thereby treatingthe mood and/or anxiety disorder.

Still further, another therapeutic system comprises a device that issurgically implanted into the subject such that the device is incommunication with a predetermined site, for example a subcallosal area.An exemplary device includes a microstimulator (i.e., Bion™ manufacturedby Advanced Bionics Corporation) in which the device contains agenerating portion and at least one electrode in a single unit. Infurther embodiments, a lead assembly is associated with at least oneelectrode of the microstimulator such that the lead can stimulate thepredetermined site not in direct contact with the microstimulator.

Other therapeutic systems include a probe that is in communication withthe predetermined site and a device that stimulates the probe therebytreating the mood and/or anxiety disorder. The probe can be, forexample, an electrode assembly (i.e., electrical stimulation lead),pharmaceutical-delivery assembly (i.e., catheters) or combinations ofthese (i.e., a catheter having at least one electrical stimulationlead). The probe is coupled to the device, for example, electricalsignal source, pharmaceutical delivery pump, or both which, in turn, isoperated to stimulate the predetermined treatment site.

The foregoing has outlined rather broadly features and/or technicaladvantages in order that the detailed description that follows may bebetter understood. Additional features and advantages will be describedhereinafter. It should be appreciated that the conception and specificembodiment disclosed may be readily utilized as a basis for modifying ordesigning other structures for carrying out the same purposes. It shouldalso be realized that such equivalent constructions do not depart fromthe appended claims. Novel features, both as to its organization andmethod of operation, together with further objects and advantages willbe better understood from the following description when considered inconnection with the accompanying figures. It is to be expresslyunderstood, however, that each of the figures is provided for thepurpose of illustration and description only and is not intended as adefinition of the limits of the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of some representative embodiments,reference is now made to the following descriptions taken in conjunctionwith the accompanying drawings.

FIGS. 1A and 1B illustrate example electrical stimulation systems.

FIGS. 2A-2D illustrate example electrical stimulation leads that may beused to stimulate a patient according to some representativeembodiments.

FIG. 3 is a coronal (front vertical) section of a human brain showingarrows directed to target areas.

FIG. 4 is a flowchart describing the general procedure.

FIGS. 5A and 5B shows a graphical analysis of scores based upon theHamilton Rating Scale for Depression after deep brain stimulationtreatment.

FIGS. 6A-6E show scans through various planes of the brain. FIG. 6Ashows a T1 MRI in the horizontal plane showing the tips (at arrows) onthe implanted lead 4 contact electrodes positioned anterior to theanterior commissure (AC), approximately 7 mm from the midline and belowthe plane of the inter-commissural line, in a patient with depression.FIG. 6B shows an axial T1 MRI in the horizontal plane of a patient withdepression implanted with chronic deep brain stimulating electrodes tostimulate subcallosal white matter and adjacent cortex includingsubgenual cingulate gyrus, particularly Brodmann area 25/Brodmann area24. FIG. 6C shows a Sagittal T1 weighted MRI, vertical through the nose,showing an implanted chronic deep brain stimulating electrode with 4contacts to stimulate subcallosal white matter and adjacent cortexincluding subgenual cingulate gyrus, particularly Brodmann area25/Brodmann area 24. The central dot shows a contact area. FIG. 6D showsa T1 weighted MRI Coronal view of a patient having scans of FIGS. 6A and6B showing right and left electrodes in the plane of the braincorresponding to the Schaltebrand and Warren atlas section plate 3 shownin FIG. 3. The central dot is the midline. FIG. 6E shows T1 weighted MRIimages of a second patient with bilateral electrodes implanted tostimulate subcallosal white matter and adjacent cortex includingsubgenual cingulate gyrus, particularly Brodmann area 25/Brodmann area24.

DETAILED DESCRIPTION

It is readily apparent to one skilled in the art that variousembodiments and modifications can be made to the representativeembodiments in this application without departing from the scope of theappended claims.

I. DEFINITIONS

As used herein, the use of the word “a” or “an” when used in conjunctionwith the term “comprising” in the claims and/or the specification maymean “one,” but it is also consistent with the meaning of “one or more,”“at least one,” and “one or more than one.” Still further, the terms“having”, “including”, “containing” and “comprising” are interchangeableand one of skill in the art is cognizant that these terms are open endedterms.

As used herein the term “affective disorders” refers to a group ofdisorders that are commonly associated with co-morbidity of depressionand anxiety symptoms.

As used herein the term “anxiety” refers to an uncomfortable andunjustified sense of apprehension that may be diffuse and unfocused andis often accompanied by physiological symptoms.

As used herein the term “anxiety disorder” refers to or connotessignificant distress and dysfunction due to feelings of apprehension,guilt, fear, etc. Anxiety disorders include, but are not limited topanic disorders, posttraumatic stress disorder, obsessive-compulsivedisorder and phobic disorders.

As used herein, the term “Brodmann area 25” refers to the defined areaof Brodmann area 25 as known by one of skill in the art, as well as thesurrounding or adjacent white matter tracts leading to and from Brodmannarea 25 and/or white matter tracts that are contiguous with Brodmannarea 25. The surrounding or adjacent white matter can include up toapproximately a 1 cm radius of Brodmann area 25.

As used herein, the term “Brodmann area 24” refers to the defined areaof Brodmann area 24 as known by one of skill in the art, as well as thesurrounding or adjacent white matter tracts leading to and from Brodmannarea 24 and/or white matter tracts that are contiguous with Brodmannarea 24. The surrounding or adjacent white matter can include up toapproximately a 1 cm radius of Brodmann area 24.

As used herein, the term “Brodmann area 9” refers to the defined area ofBrodmann area 9 as known by one of skill in the art, as well as thesurrounding or adjacent white matter tracts leading to and from Brodmannarea 9 and/or white matter tracts that are contiguous with Brodmann area9. The surrounding or adjacent white matter can include up toapproximately a 1 cm radius of Brodmann area 9.

As used herein, the term “Brodmann area 10” refers to the defined areaof Brodmann area 10 as known by one of skill in the art, as well as thesurrounding or adjacent white matter tracts leading to and from Brodmannarea 10 and/or white matter tracts that are contiguous with Brodmannarea 10. The surrounding or adjacent white matter can include up toapproximately a 1 cm radius of Brodmann area 10.

As used herein the term “depression” refers to a morbid sadness,dejection, or melancholy.

As used herein, the term “in communication” refers to one or moreelectrical stimulation leads and/or catheters being adjacent, in closeproximity, or directly next to, or in direct contact or directly in thepredetermined stimulation site. Thus, one of skill in the artunderstands that the one or more electrical stimulation leads and/orcatheters are “in communication” with the predetermined site of thebrain if the stimulation results in a modulation of neuronal activityassociated with a site. Still further, “in communication” with braintissue encompasses surrounding or adjacent white matter tracts or fibersleading to and from the brain tissue and/or white matter tracts orfibers that are contiguous with the brain tissue.

As used herein the term “limbic system” encompasses the amygdala,hippocampus, septum, cingulate gyrus, cingulate cortex, hypothalamus,epithalamus, anterior thalamus, mammillary bodies, and fornix. Thelimbic system has connections throughout the brain, more particularlywith the primary sensory cortices, including the rhinencephalon forsmell, the autonomic nervous system via the hypothalamus, and memoryareas. Yet further, the limbic system is involved in mood, emotion andthought.

As used herein the term “mania” or “manic” refers to a disordered mentalstate of extreme excitement.

As used herein the term “mood” refers to an internal emotional state ofa person.

As used herein the term “mood disorder” is typically characterized bypervasive, prolonged, and disabling exaggerations of mood and affectthat are associated with behavioral, physiologic, cognitive,neurochemical and psychomotor dysfunctions. The major mood disordersinclude, but are not limited to major depressive disorder (also known asunipolar disorder), bipolar disorder (also known as manic depressiveillness or bipolar depression), dysthymic disorder. Other mood disordersmay include, but are not limited to major depressive disorder,psychotic; major depressive disorder, melancholic; major depressivedisorder, seasonal pattern; postpartum depression; brief recurrentdepression; late luteal phase dysphoric disorder (premenstrualdysphoria); and cyclothymic disorder.

As used herein the term “modulate” refers to the ability to regulatepositively or negatively neuronal activity. Thus, the term modulate canbe used to refer to an increase, decrease, masking, altering, overridingor restoring neuronal activity. Modulation of neuronal activity affectspsychological and/or psychiatric activity of a subject.

As used herein, the term “neuronal” refers to a neuron which is amorphologic and functional unit of the brain, spinal column, andperipheral nerves.

As used herein, the term “pharmaceutical” refers to a chemical or agentthat is used as a drug. Thus, the term pharmaceutical and drug areinterchangeable.

As used herein, the term “stimulate” or “stimulation” refers toelectrical, chemical, and/or magnetic stimulation that modulates thepredetermined sites in the brain.

As used herein, the term “subcallosal area” includes the medial graymatter and white matter under the corpus callosum, as well as the whitematter tracts that are associated with the subcallosal area. Associatedwhite matter tracts includes the surrounding or adjacent white mattertracts leading to or from a subcallosal area or white matter tracts thatare contiguous with the subcallosal area. For the purposes of thepresent application, the subcallosal area includes the following graymatter and the white matter tracts, as well as the white matter tractsthat are associated with or leading to or from the following areas:subgenual cingulate area, subcallosal cingulate area, ventral/medialprefrontal cortex area, ventral/medial white matter, Brodmann area 24,Brodmann area 25, and/or Brodmann area 10. The surrounding or adjacentwhite matter tracts can include up to approximately a 1 cm radius of thesubcallosal area.

As used herein, the term “subgenual cingulate area” includes the graymatter and white matter tracts associated with the subgenual cingulatearea, the white matter tracts that surround or adjacent to the subgenualcingulate area, or the white matter tracts that lead to or from thesubgenual cingulate area. The subgenual cingulate area includes Brodmannarea 25 and the subgenual portion of Brodmann area 24. The surroundingor adjacent white matter can include up to approximately a 1 cm radiusof the subgenual cingulate area

As used herein, the term “treating” and “treatment” refers to modulatingcertain areas of the brain so that the subject has an improvement in thedisease, for example, beneficial or desired clinical results. Forpurposes of this application, beneficial or desired clinical resultsinclude, but are not limited to, alleviation of symptoms, diminishmentof extent of disease, stabilized (i.e., not worsening) state of disease,delay or slowing of disease progression, amelioration or palliation ofthe disease state, and remission (whether partial or total), whetherdetectable or undetectable. One of skill in the art realizes that atreatment may improve the disease condition, but may not be a completecure for the disease.

II. ELECTRICAL STIMULATION DEVICES

FIGS. 1A and 1B illustrate example electrical stimulation systems ordevices 10 used to provide deep brain stimulation. Stimulation system 10generates and applies a stimulus to a target area of the brain, forexample, a target area of a subcallosal area, more particularly, asubgenual cingulate area. Still further, the target area can compriseBrodmann area 25 and/or Brodmann area 24. In general terms, stimulationsystem 10 includes an implantable electrical stimulation source 12 andan implantable electrical stimulation lead 14 for applying thestimulation signal to the target brain tissue. In operation, both ofthese primary components are implanted in the person's body. Stimulationsource 12 is coupled to a connecting portion 16 of electricalstimulation lead 14. Stimulation source 12 controls the electricalsignals transmitted to electrodes 18 located on a stimulating portion 20of electrical stimulation lead 14, located adjacent the target braintissue, according to suitable signal parameters (i.e., duration,intensity, frequency, etc.). A doctor, the patient, or another user ofstimulation source may directly or indirectly input signal parametersfor controlling the nature of the electrical stimulation provided.

Another exemplary stimulation system or device includes amicrostimulator (i.e., Bion™, manufactured by Advanced BionicsCorporation) in which the device contains a signal generating portionand at least one electrode in a the same unit or single unit, as definedin U.S. Pat. Nos. 6,051,017; 6,735,475 and 6,735,474, each of which areincorporated herein in its entirety. In further embodiments, a leadassembly is associated with at least one electrode of themicrostimulator such that the lead can stimulate the predetermined sitenot in contact with the microstimulator.

In one embodiment, as shown in FIG. 1A, stimulation source 12 includesan implantable pulse generator (IPG). One of skill in the art is awarethat any commercially available implantable pulse generator can be usedin the present application, as well as a modified version of anycommercially available pulse generator. Thus, one of skill in the artwould be able to modify an IPG to achieve the desired results. Anexemplary IPG is one that is manufactured by Advanced NeuromodulationSystems, Inc., such as the Genesis® System, part numbers 3604, 3608,3609, and 3644. Another example of an IPG is shown in FIG. 1B, whichshows stimulation source 12 including an implantable wireless receiver.An example of a wireless receiver may be one manufactured by AdvancedNeuromodulation Systems, Inc., such as the Renew® System, part numbers3408 and 3416. The wireless receiver is capable of receiving wirelesssignals from a wireless transmitter 22 located external to the person'sbody. The wireless signals are represented in FIG. 1B by wireless linksymbol 24. A doctor, the patient, or another user of stimulation source12 may use a controller 26 located external to the person's body toprovide control signals for operation of stimulation source 12.Controller 26 provides the control signals to wireless transmitter 22,wireless transmitter 22 transmits the control signals and power to thewireless receiver of stimulation source 12, and stimulation source 12uses the control signals to vary the signal parameters of electricalsignals transmitted through electrical stimulation lead 14 to thestimulation site. An example wireless transmitter may be onemanufactured by Advanced Neuromodulation Systems, Inc., such as theRenew® System, part numbers 3508 and 3516.

FIGS. 2A through 2D illustrate example electrical stimulation leads 14that may be used to provide electrical stimulation to an area of thebrain, however, one of skill in the art is aware that any suitableelectrical lead may be used. As described above, each of the one or moreleads 14 incorporated in stimulation system 10 includes one or moreelectrodes 18 adapted to be positioned near the target brain tissue andused to deliver electrical stimulation energy to the target brain tissuein response to electrical signals received from stimulation source 12. Apercutaneous lead 14, such as example leads shown in FIG. 2A-2D,includes one or more circumferential electrodes 18 spaced apart from oneanother along the length of lead 14. Circumferential electrodes 18 emitelectrical stimulation energy generally radially in all directions.

III. IMPLANTATION OF ELECTRICAL STIMULATION DEVICES

While not being bound by the description of a particular procedure,patients who are to have an electrical stimulation lead or electrodeimplanted into the brain, generally, first have a stereotactic headframe, such as the Leksell, CRW, or Compass, mounted to the patient'sskull by fixed screws. However, frameless techniques may also be used.Subsequent to the mounting of the frame, the patient typically undergoesa series of magnetic resonance imaging sessions, during which a seriesof two dimensional slice images of the patient's brain are built up intoa quasi-three dimensional map in virtual space. This map is thencorrelated to the three dimensional stereotactic frame of reference inthe real surgical field. In order to align these two coordinate frames,both the instruments and the patient must be situated in correspondenceto the virtual map. The current way to do this is to rigidly mount thehead frame to the surgical table. Subsequently, a series of referencepoints are established to relative aspects of the frame and thepatient's skull, so that either a person or a computer software systemcan adjust and calculate the correlation between the real world of thepatient's head and the virtual space model of the patient's MRI scans.The surgeon is able to target any region within the stereotactic spaceof the brain with precision (i.e., within 1 mm). Initial anatomicaltarget localization is achieved either directly using the MRI images, orindirectly using interactive anatomical atlas programs that map theatlas image onto the stereotactic image of the brain. As is described ingreater detail below, the anatomical targets may be stimulated directlyor affected through stimulation in another region of the brain.

With reference to FIG. 3, this shows the position of the subcallosalarea having coordinates derived from the Schaltenbrand and Wahren Atlasplate 3 coronal section through the brain are 6-7 mm from the midline(range 2-14 mm), 29 mm anterior to the mid-commissural point range(20-40) and 5 mm (range 0-10 mm) below the intra-commissural line.Referring to FIG. 3, arrow 1 points to the subgenual cingulate area,more particularly Brodmann area 25; arrow 2 points to the gyrus rectusarea; arrow 3 points to the subcaudate area; and arrow 4 points to theorbitofrontal area.

Based upon the coordinates derived or described above, the electricalstimulation lead 14 can be positioned in the brain. Typically, aninsertion cannula for electrical stimulation lead 14 is inserted throughthe burr hole into the brain, but a cannula is not required. Forexample, a hollow needle may provide the cannula. The cannula andelectrical stimulation lead 14 may be inserted together or lead 14 maybe inserted through the cannula after the cannula has been inserted.

Once an electrical stimulation lead, such as lead 14, has beenpositioned in the brain, the lead is uncoupled from any stereotacticequipment present, and the cannula and stereotactic equipment areremoved. Where stereotactic equipment is used, the cannula may beremoved before, during, or after removal of the stereotactic equipment.Connecting portion 16 of electrical stimulation lead 14 is laidsubstantially flat along the skull. Where appropriate, any burr holecover seated in the burr hole may be used to secure electricalstimulation lead 14 in position and possibly to help prevent leakagefrom the burr hole and entry of contaminants into the burr hole. Exampleburr hole covers that may be appropriate in certain embodiments areillustrated and described in co-pending U.S. Application Nos. 60/528,604and 60/528,689, both filed Dec. 11, 2003 and entitled “ElectricalStimulation System and Associated Apparatus for Securing an ElectricalStimulation Lead in Position in a Person's Brain”, each of which areincorporated herein in its entirety.

Once electrical stimulation lead 14 has been inserted and secured,connecting portion 16 of lead 14 extends from the lead insertion site tothe implant site at which stimulation source 12 is implanted. Theimplant site is typically a subcutaneous pocket formed to receive andhouse stimulation source 12. The implant site is usually positioned adistance away from the insertion site, such as near the chest, below theclavicle or alternatively near the buttocks or another place in thetorso area. Once all appropriate components of stimulation system areimplanted, these components may be subject to mechanical forces andmovement in response to movement of the person's body. A doctor, thepatient, or another user of stimulation source may directly orindirectly input signal parameters for controlling the nature of theelectrical stimulation provided.

Although example steps are illustrated and described, the presentapplication contemplates two or more steps taking place substantiallysimultaneously or in a different order. In addition, the presentapplication contemplates using methods with additional steps, fewersteps, or different steps, so long as the steps remain appropriate forimplanting an example stimulation system into a person for electricalstimulation of the person's brain.

IV. INFUSION PUMPS

In further embodiments, it may be desirable to use a drug deliverysystem independent of or in combination with electrical stimulation ofthe brain. Drug delivery may be used independent of or in combinationwith a lead/electrode to provide electrical stimulation and chemicalstimulation. When used, the drug delivery catheter is implanted suchthat the proximal end of the catheter is coupled to a pump and adischarge portion for infusing a dosage of a pharmaceutical or drug.Implantation of the catheter can be achieved by combining data from anumber of sources including CT, MRI or conventional and/or magneticresonance angiography into the stereotactic targeting model. Thus,without being bound to a specific procedure, implantation of thecatheter can be achieved using similar techniques as discussed above forimplantation of electrical leads, which is incorporated herein. Thedistal portion of the catheter can have multiple orifices to maximizedelivery of the pharmaceutical while minimizing mechanical occlusion.The proximal portion of the catheter can be connected directly to a pumpor via a metal, plastic, or other hollow connector, to an extendingcatheter.

Any suitable type of infusion pump can be used to deliver an appropriatetherapeutic agent. For example, “active pumping” devices or so-calledperistaltic pumps are described in U.S. Pat. Nos. 4,692,147, 5,840,069,and 6,036,459, which are incorporated herein by reference in theirentirety. Peristaltic pumps are used to provide a metered amount of adrug in response to an electronic pulse generated by control circuitryassociated within the device. An example of a commercially availableperistaltic pump is SynchroMed® implantable pump from Medtronic, Inc.,Minneapolis, Minn.

Other pumps that may be used include accumulator-type pumps, for examplecertain external infusion pumps from Minimed, Inc., Northridge, Calif.and Infusaid® implantable pump from Strato/Infusaid, Inc., Norwood,Mass. Passive pumping mechanisms can be used to release an agent in aconstant flow or intermittently or in a bolus release. Passive typepumps include, for example, but are not limited to gas-driven pumpsdescribed in U.S. Pat. Nos. 3,731,681 and 3,951,147; and drive-springdiaphragm pumps described in U.S. Pat. Nos. 4,772,263, 6,666,845,6,620,151 which are incorporated by reference in its entirety. Pumps ofthis type are commercially available, for example, Model 3000® fromArrow International, Reading, Pa. and IsoMed® from Medtronic, Inc.,Minneapolis, Minn.; AccuRx® pump from Advanced Neuromodulation Systems,Inc., Plano, Tex.

Instances in which chemical and electrical stimulation will beadministered to the subject, a catheter having electrical leads may beused, similar to the ones described in U.S. Pat. Nos. 6,176,242;5,423,877; 5,458,631 and 5,119,832, each of which are incorporatedherein by reference in its entirety.

V. IDENTIFYING A SUBJECT WITH AN AFFECTIVE DISORDER

Subjects can be selected, identified and/or diagnosed based upon theaccumulation of physical, chemical, and historical behavioral data oneach patient. One of skill in the art is able to perform the appropriateexaminations to accumulate such data. One type of examination caninclude neurological examinations, which can include mental statusevaluations, which can further include a psychiatric assessment. Othertypes of examinations can include, but are not limited to, motorexamination, cranial nerve examination, and neuropsychological tests(i.e., Minnesota Multiphasic Personality Inventory, Beck DepressionInventory, or Hamilton Rating Scale for Depression).

In addition to the above examinations, imaging techniques can be used todetermine normal and abnormal brain function that can result indisorders. Functional brain imaging allows for localization of specificnormal and abnormal functioning of the nervous system. This includeselectrical methods such as electroencephalography (EEG),magnetoencephalography (MEG), single photon emission computed tomography(SPECT), as well as metabolic and blood flow studies such as functionalmagnetic resonance imaging (fMRI), and positron emission tomography(PET) which can be utilized to localize brain function and dysfunction.

VI. TREATMENT OF AN AFFECTIVE DISORDER

Initially, there is an impetus to treat psychiatric disorders withdirect modulation of activity in that portion of the brain causing thepathological behavior. In this regard, there have been a large number ofanatomical studies that have helped to identify the neural structuresand their precise connections which are implicated in psychiatricactivity/disorders. These are the structures that are functioningabnormally and manifesting in psychiatric/behavioral/addictiondisorders. Numerous anatomical studies from autopsies, animal studies,and imaging such as computerized tomography (CT) scans, and magneticresonance imaging (MRI) scans have demonstrated the role of thesestructures and their connections in psychiatric activity/disorders. Inaddition to these anatomical studies, a number of physiologicaltechniques and diagnostic tools are used to determine the physiologicalaberrations underlying these disorders. This includes electrical methodssuch as electroencephalography (EEG), magnetoencephalography (MEG), aswell as metabolic and blood flow studies such as functional magneticresonance imaging (fMRI), and positron emission tomography (PET). Thecombination of the anatomical and physiological studies have providedincreased insight into our understanding of the structures which areinvolved in the normal functioning or activity of the brain and theabnormal functioning manifesting in psychiatric, behavioral andaddiction disorders.

Accordingly, the present application relates to modulation of neuronalactivity to affect psychological or psychiatric activity and/or mentalactivity. The present application finds particular application in themodulation of neuronal function or processing to effect a functionaloutcome. The modulation of neuronal function is particularly useful withregard to the prevention, treatment, or amelioration of psychiatric,psychological, conscious state, behavioral, mood, and thought activity(unless otherwise indicated these will be collectively referred toherein as “psychological activity” or “psychiatric activity” or “mentalactivity”). When referring to a pathological or undesirable conditionassociated with the activity, reference may be made to “psychiatricdisorder” or “psychological disorder” instead of psychiatric orpsychological activity. Although the activity to be modulated usuallymanifests itself in the form of a disorder such as a mood disorder(i.e., major depressive disorder, bipolar disorder, and dysthymicdisorder) or an anxiety disorder (i.e., panic disorder, posttraumaticstress disorder, obsessive-compulsive disorder and phobic disorder), itis to be appreciated that some representative embodiments may also findapplication in conjunction with enhancing or diminishing anyneurological or psychiatric function, not just an abnormality ordisorder. Psychiatric activity that may be modulated can include, butnot be limited to, normal functions such as alertness, conscious state,drive, fear, anger, anxiety, euphoria, sadness, and the fight or flightresponse.

The present application finds particular utility in its application tohuman psychological or psychiatric activity/disorder. However, it isalso to be appreciated that the present application is applicable toother animals which exhibit behavior that is modulated by the brain.This may include, for example, rodents, primates, canines, felines,elephants, dolphins, etc. Utilizing some embodiments, one skilled in theart may be able to modulate the functional outcome of the brain toachieve a desirable result.

One technique that offers the ability to affect neuronal function is thedelivery of electrical, chemical, and/or magnetic stimulation forneuromodulation directly to target tissues via an implanted devicehaving a probe. The probe can be a stimulation lead or electrodeassembly or drug-delivery catheter, or any combination thereof. Theelectrode assembly may be one electrode, multiple electrodes, or anarray of electrodes in or around the target area. The proximal end ofthe probe can be coupled to a device, such as an electrical signalsource, pharmaceutical delivery pump, or both which, in turn, isoperated to stimulate the predetermined treatment site. In certainembodiments, the probe can be incorporated into the device such that theprobe and the signal generating device are a single unit.

Certain embodiments involve a method of treating a mood and/or anxietydisorder comprising the steps of: surgically implanting an electricalstimulation lead having a proximal end and a stimulation portion,wherein after implantation the stimulation portion is in communicationwith a predetermined site; coupling the proximal end of the lead to asignal generator; and generating an electrical signal with the signalgenerator to modulate the predetermined site thereby treating the moodand/or anxiety disorder.

In further embodiments, neuromodulation of the predetermined site can beachieved using magnetic stimulation. One such system that can beemployed and that is well known in the art is described in U.S. Pat. No.6,425,852, which is incorporated herein by reference in its entirety.

The therapeutic system or deep brain stimulation system is surgicallyimplanted as described in the above sections. One of skill in the art iscognizant that a variety of electrodes or electrical stimulation leadsmay be utilized. It is desirable to use an electrode or lead thatcontacts or conforms to the target site for optimal delivery ofelectrical stimulation. One such example, is a single multi contactelectrode with eight contacts separated by 2½ mm each contract wouldhave a span of approximately 2 mm. Another example is an electrode withtwo 1 cm contacts with a 2 mm intervening gap. Yet further, anotherexample of an electrode that can be used is a 2 or 3 branchedelectrode/catheter to cover the predetermined site or target site. Eachone of these three pronged catheters/electrodes have four contacts 1-2mm contacts with a center to center separation of 2 of 2.5 mm and a spanof 1.5 mm. Similar designs with catheters to infuse drugs with singleoutlet pore at the extremities of these types of catheters or alongtheir shaft may also be designed and used.

Still further, the present application extends to methods oftransplanting cells into a predetermined site to treat mood and/oranxiety disorders. It is envisioned that the transplanted cells canreplace damaged, degenerating or dead neuronal cells, deliver abiologically active molecule to the predetermined site or to amelioratea condition and/or to enhance or stimulate existing neuronal cells. Suchtransplantation methods are described in U.S. Application No.US20040092010, which is incorporated herein by reference in itsentirety.

Cells that can be transplanted can be obtained from stem cell lines(i.e., embryonic stem cells, non-embryonic stem cells, etc.) and/orbrain biopsies, including tumor biopsies, autopsies and from animaldonors. (See U.S. Application No. US20040092010; U.S. Pat. Nos.5,735,505 and 6,251,669; Temple, Nature Reviews 2:513-520 (2000);Bjorklund and Lindvall, Nat. Neurosci. 3:537-544 (2000)), each of whichis incorporated herein by reference in its entirety). Brain stem cellscan then be isolated (concentrated) from non-stem cells based onspecific “marker” proteins present on their surface. In one suchembodiment, a fluorescent antibody specific for such a marker can beused to isolate the stem cells using fluorescent cell sorting (FACS). Inanother embodiment an antibody affinity column can be employed.Alternatively, distinctive morphological characteristics can beemployed.

The predetermined site or target area is a subcallosal area, morepreferably, the subgenual cingulate area, and more preferably Brodmannarea 25/Brodmann area 24. Stimulation of a subcallosal area (i.e.,subgenual cingulate area or Brodmann area 25/Brodmann area 24) and/orthe surrounding or adjacent white matter tracts leading to or from thesubcallosal area or white matter tracts that are contiguous with thesubcallosal area results in changes that alleviate or improve the moodand/or anxiety disorder of the subject. It is contemplated thatmodulating a subcallosal area, more particularly a subgenual cingulatearea, can result in increasing, decreasing, masking, altering,overriding or restoring neuronal activity resulting in treatment of themood and/or anxiety disorder. Yet further stimulation of a subgenualcingulate area, more particularly Brodmann area 25, results inmodulation of neuronal activity of other areas of the brain, forexample, Brodmann area 9, Brodmann area 10, Brodmann area 24, thehypothalamus, and the brain stem.

Using the therapeutic stimulation system, the predetermined site ortarget area is stimulated in an effective amount or effective treatmentregimen to decrease, reduce, modulate or abrogate the mood and/oranxiety disorder. Thus, a subject is administered a therapeuticallyeffective stimulation so that the subject has an improvement in theparameters relating to the affective disorder including subjectivemeasures such as, for example, neurological examinations andneuropsychological tests (i.e., Minnesota Multiphasic PersonalityInventory, Beck Depression Inventory, Mini-Mental Status Examination(MMSE), Hamilton Rating Scale for Depression, Wisconsin Card SortingTest (WCST), Tower of London, Stroop task, MADRAS, CGI, N-BAC, orYale-Brown Obsessive Compulsive score (Y-BOCS)), motor examination, andcranial nerve examination, and objective measures including use ofadditional psychiatric medications, such as anti-depressants, or otheralterations in cerebral blood flow or metabolism and/or neurochemistry.The improvement is any observable or measurable improvement. Thus, oneof skill in the art realizes that a treatment may improve the patientcondition, but may not be a complete cure of the disease.

Treatment regimens may vary as well, and often depend on the health andage of the patient. Obviously, certain types of disease will requiremore aggressive treatment, while at the same time, certain patientscannot tolerate more taxing regimens. The clinician will be best suitedto make such decisions based on the known subject's history.

According to one embodiment, the target site is stimulated usingstimulation parameters such as, pulse width of about 1 to about 500microseconds, more preferable, about 1 to about 90 microseconds;frequency of about 1 to about 300 Hz, more preferably, about 100 toabout 185 Hz; and voltage of about 0.5 to about 10 volts, morepreferably about 1 to about 10 volts. It is known in the art that therange for the stimulation parameters may be greater or smaller dependingon the particular patient needs and can be determined by the physician.Other parameters that can be considered may include the type ofstimulation for example, but not limited to acute stimulation, subacutestimulation, and/or chronic stimulation.

It is envisioned that stimulation of a subcallosal area and/or theadjacent white matter modulates other targets in the limbic-corticalcircuit or pathway thereby improving any dysfunctional limbic-corticalcircuits resulting in an improvement or alleviation or providingremission of depression and/or anxiety in the treated subjects. Othersuch improvements can be sensations of calm, tranquility, peacefulness,increased energy and alertness, improved mood, improvement in attentionand thinking, improvement in motor speed, improvement in mental speedand in spontaneity of speech, improved sleep, improved appetite,improved limbic behavior, increased motivation, decreases in anxiety,decreases in repetitive behavior, impulses, obsessions, etc.

For purposes of this application, beneficial or desired clinical resultsinclude, but are not limited to, alleviation of symptoms, diminishmentof extent of disease, stabilized (i.e., not worsening) state of disease,delay or slowing of disease progression, amelioration or palliation ofthe disease state, and remission (whether partial or total), whetherobjective or subjective.

FIG. 4 summarizes the general procedure according to one representativeembodiment. Any of the above described methods can be used to identify asubject or diagnose a subject that suffers from an affective disorder(100). Once the subject is identified, a stimulation device is implanted(200) into the subject such that the subcallosal area of the subject'sbrain is stimulated (300). After the target area has been stimulated(i.e., electrical, chemical or magnetic stimulation), the subject isevaluated to determine the change in the affective disorder. One ofskill in the art realizes that the present application is not bound bythe described methods or devices and that any method or device thatwould result in neuromodulation of the subcallosal area could be used.

VII. COMBINATION TREATMENT

In order to increase the effectiveness of the electrical stimulationmethod, it may be desirable to combine electrical stimulation withchemical stimulation to treat the mood and/or anxiety disease.

In one preferred alternative, an implantable signal generator andelectrical stimulating lead and an implantable pump and catheter(s) areused to deliver electrical stimulation and/or one or more stimulatingdrugs to the above mentioned areas as a treatment for mood and/oranxiety disorders.

Herein, stimulating drugs comprise medications, anesthetic agents,synthetic or natural peptides or hormones, neurotransmitters, cytokinesand other intracellular and intercellular chemical signals andmessengers, and the like. In addition, certain neurotransmitters,hormones, and other drugs are excitatory for some tissues, yet areinhibitory to other tissues. Therefore, where, herein, a drug isreferred to as an “excitatory” drug, this means that the drug is actingin an excitatory manner, although it may act in an inhibitory manner inother circumstances and/or locations. Similarly, where an “inhibitory”drug is mentioned, this drug is acting in an inhibitory manner, althoughin other circumstances and/or locations, it may be an “excitatory” drug.In addition, stimulation of an area herein includes stimulation of cellbodies and axons in the area.

Similarly, excitatory neurotransmitter agonists (i.e., norepinephrine,epinephrine, glutamate, acetylcholine, serotonin, dopamine), agoniststhereof, and agents that act to increase levels of an excitatoryneurotransmitter(s) (i.e., edrophonium; Mestinon; trazodone; SSRIs(i.e., flouxetine, paroxetine, sertraline, citalopram and fluvoxamine);tricyclic antidepressants (i.e., imipramine, amitriptyline, doxepin,desipramine, trimipramine and nortriptyline), monoamine oxidaseinhibitors (i.e., phenelzine, tranylcypromine, isocarboxasid)),generally have an excitatory effect on neural tissue, while inhibitoryneurotransmitters (i.e., dopamine, glycine, and gamma-aminobutyric acid(GABA)), agonists thereof, and agents that act to increase levels of aninhibitory neurotransmitter(s) generally have an inhibitory effect.(Dopamine acts as an excitatory neurotransmitter in some locations andcircumstances, and as an inhibitory neurotransmitter in other locationsand circumstances.) However, antagonists of inhibitory neurotransmitters(i.e., bicuculline) and agents that act to decrease levels of aninhibitory neurotransmitter(s) have been demonstrated to excite neuraltissue, leading to increased neural activity. Similarly, excitatoryneurotransmitter antagonists (i.e., prazosin, and metoprolol) and agentsthat decrease levels of excitatory neurotransmitters may inhibit neuralactivity. Yet further, lithium salts and anesthetics (i.e., lidocane)may also be used in combination with electrical stimulation.

VIII. EXAMPLES

The following examples are included to demonstrate preferredembodiments, more particularly methods and procedures, according to someembodiments. It should be appreciated by those of skill in the art thatthe techniques disclosed in the examples which follow representtechniques discovered by the inventor to function well in the practiceof some embodiments of the invention, and thus can be considered toconstitute preferred modes of practice. However, those of skill in theart should, in light of the present disclosure, appreciate that manychanges can be made in the specific embodiments which are disclosed andstill obtain a like or similar result without departing from the spiritand scope of the appended claims.

Example 1 Patient Selection

Five patients were selected for electrical stimulation of the brain.Patients were selected based upon various demographics, family historyof depression (FHx), age of onset, episodes of depression per year, themedications, other therapies, and the Hamilton rating score, as shown inTable 1. (Note “Dur yr” means duration in years).

As is known in the art, a score above 7 on the Hamilton 17 scale (“H17”)is an indication of depression. A 50% change in the H17 scale score offrom the initial baseline score is considered a clinical response, whilea score of less than 7 is considered clinical remission.

TABLE 1 Patient Demographic Age Dur Epi PT Sex Age FHx onset Yr yr MedsECT CBT IPT H17 dx A F 48 Y 18 20 2.5 1,2,4 N N Y 29 UP B F 45 Y 21 24 61,2,3,5 Y Y Y 27 UP C M 37 Y 20 17 10 1,2 Y Y Y 26 UP D M 48 Y 36 12 51,2,5 Y Y Y 24 UP E M 59 N 45 15 3 1,2,3 Y N Y 20 BPII Mean 47 28 18 525 Meds: 1 = SSRI, 2 = bupropion, 3 = atypical antipsychotics, 4 =stimulates, 5 = other (benzo, and anticonvulsants).

Example 2 Surgical Procedure

Under local anesthesia, a stereotactic frame was first placed on thepatient's head, followed by acquisition of an MRI (Magnetic ResonanceImaging) scan to localize the target region. Patients were then taken tothe operating room where, under local anesthesia, two burr holes wereplaced behind the hairline. Stereotactic coordinates were derived fromthe pre-op MRI. The coordinates of this target derived from theSchaltenbrand and Wahren Atlas plate 3 (FIG. 3) were 6-7 mm from themidline (range 2-14 mm), 29 mm anterior to the mid-commissural pointrange 20-40) and 5 mm (range 0-10 mm) below the intra-commissural line.

Once the target sites were identified, two multi contact electrodes weredelivered, one in each hemisphere. The electrodes were connected to astimulating pulse generator.

With the patient's participation, each electrode contact was stimulatedand acute changes in behavior was assessed using self report and moodrating scales, such as POMS, PANAS, sadness, anxiety and general wellbeing, self-report, and mood, motor and cognitive scales, such as,finger tapping, verbal fluency. As either positive or negative changesin mood might occur, the relationship between the specific stimulationsite and the resulting behavior was carefully documented. Following atesting session to help in optimal target selection and adjustment ofthe position of the electrode contacts, the incisions were closed andpatients taken to the intensive care unit for recovery from surgery.

At anytime after the surgery for implantation of the electrodes,patients underwent a second procedure (˜45 mins under generalanesthesia) to connect the electrodes to a self contained subcutaneousgenerator device placed below the clavicle and connected to theelectrodes in the head. After 2-3 days, the patients was discharged homeon their regular antidepressant regime with the stimulator turned OFF.

Example 3 Outpatient Programming and Clinical Follow-Up

Patients returned for generator device programming. There were severalparameters that were tested, namely, which electrode contact was to bestimulated, the polarity of stimulation, the frequency and pulse widthof stimulation, etc.

The electrode programming was done on an outpatient basis and involved aseries of trials over the course of a week. Electrode contacts thatproduced acute behavioral changes or fMRI signal changes in thesubgenual cingulate area (Brodmann area 25) were tried first. Once basicparameters were set, adjustments were made periodically until a stableprogram was established.

Once final stimulation parameters were established, psychiatric symptomswere monitored on a monthly basis. Clinical ratings were quantifiedusing Beck, Hamilton, CGI, and Quality of Life Scales and SerialNeuropsychological Testing. Serial Neuropsychological Testing and PETstudies were performed at 8 weeks and 6 months. General cognitiveperformance and detailed frontal lobe functioning was assessed. The testbattery was designed to differentiate dorsolateral, superior medial, andventrolateral/orbital frontal behaviors which was differently affectedby activation or disruption of the target areas with electricalstimulation. Serial testing allowed differentiation between earlysurgical effects, chronic stimulation effects, and correlations withmood change.

FIG. 5A and FIG. 5B show the results of the Hamilton Scale Scores after6 months of stimulation for the first five subjects.

Thus, stimulation in a subcallosal white matter area in communicationwith Brodmann area 25 leads to changes in the activity of Brodmann area25, the dorsal/lateral frontal lobe (Brodmann areas 9 and 6),dorsal/medial frontal lobe (Brodmann areas 9 and 10), anterior cingulatearea (Brodmann area 24), orbital frontal cortex (Brodmann areas 10 and11), the hypothalamus, brain stem and other target areas such asupstream, downstream or remote cortical and subcortical regions.

Example 4 Mapping Using fMRI

Within 1-5 days of the initial electrode surgery, fMRI scans wereperformed during successive stimulation of each electrode contact. fMRIwas used as an additional means of mapping the differences in activityof the electrodes. fMRI was not required because the optimal electrodewas determined based upon clinical observations during the operation andoperatively, as described above.

This procedure was used to further define the differential projectionfields mediating acute changes in behavior initiated by a particularstimulation site. Even without acute changes in behavior, these mapsallowed discrimination of subtle differences in pathways served bystimulation of different white matter tracts within the stimulationfield of each electrode. These results were also useful in guidingselection of the optimal site for chronic stimulation, particularly ifchanges with some but not all electrodes were seen in the targetsubgenual cingulate area.

Imaging was performed on a 1.5 T scanner using methods proven safe forpatients with implanted electrodes and delivery catheters (FIG. 6A-6E).Whole brain samples using spiral acquisition were repeated every 3.52seconds. One cycle was 120 seconds of stimulation and 120 seconds rest.A block of 4 cycles was acquired for the best and worst contact pairswithin each hemisphere based on behavior changes in the operating roomand post-operatively. The electrodes were activated using atranscutaneous lead connected to a pulse generator outside the imagingroom. Patients rated mood (pos/neg) on a 1-5 scale by button push andauditory prompt following each cycle. Analyses addressed differences ONvs OFF for each contact and changes over multiple cycles.

REFERENCES

All patents and publications mentioned in the specifications areindicative of the levels of those skilled in the art to which theapplication pertains. All patents and publications are hereinincorporated by reference to the same extent as if each individualpublication was specifically and individually indicated to beincorporated by reference.

-   Bjorklund and Lindvall, Nat. Neurosci. 3:537-544 (2000)-   Drevets et al., Nature 386:824-7, 1997.-   Ebmeier et al., Br J Psychiatry, 170:77-81, 1997.-   Galynker et al., J Nucl Med., 39:608-12, 1998.-   Temple, Nature Reviews 2:513-520 (2000)-   U.S. Pat. No. 3,731,681-   U.S. Pat. No. 3,951,147-   U.S. Pat. No. 4,692,147-   U.S. Pat. No. 4,772,263-   U.S. Pat. No. 5,119,832-   U.S. Pat. No. 5,263,480-   U.S. Pat. No. 5,299,569-   U.S. Pat. No. 5,423,877-   U.S. Pat. No. 5,458,631-   U.S. Pat. No. 5,470,846-   U.S. Pat. No. 5,540,734-   U.S. Pat. No. 5,735,505-   U.S. Pat. No. 5,840,069-   U.S. Pat. No. 6,016,449-   U.S. Pat. No. 6,036,459-   U.S. Pat. No. 6,051,017-   U.S. Pat. No. 6,176,242-   U.S. Pat. No. 6,251,669-   U.S. Pat. No. 6,425,852-   U.S. Pat. No. 6,609,031-   U.S. Pat. No. 6,620,151-   U.S. Pat. No. 6,666,845-   U.S. Pat. No. 6,735,474-   U.S. Pat. No. 6,735,475-   U.S. Publication No. US20040092010

Although some embodiments and advantages have been described in detail,it should be understood that various changes, substitutions andalterations can be made herein without departing from the appendedclaims. Moreover, the scope of the present application is not intendedto be limited to the particular embodiments of the process, machine,manufacture, composition of matter, means, methods and steps describedin the specification. As one will readily appreciate from thedisclosure, processes, machines, manufacture, compositions of matter,means, methods, or steps, presently existing or later to be developedthat perform substantially the same function or achieve substantiallythe same result as the corresponding embodiments described herein may beutilized. Accordingly, the appended claims are intended to includewithin their scope such processes, machines, manufacture, compositionsof matter, means, methods, or steps.

We claim:
 1. A method for the treatment of depression in a patient, themethod comprising: implanting a stimulation lead and an implantablepulse generator in the patient, wherein the implanting comprisesintraoperatively determining an effect on mood of the patient byelectrical stimulation on respective electrodes of the stimulation leadto gray and white matter inferior to the corpus callosum and posteriorto the anterior most portion of the genu of the corpus callosum; andadministering, after implant, electrical stimulation from theimplantable pulse generator to gray and white matter inferior to thecorpus callosum and posterior to the anterior most portion of the genuof the corpus callosum to decrease or substantially ameliorate thedepression using one or more electrodes of the stimulation lead.
 2. Themethod of claim 1 wherein at least one electrode of the stimulation leadis positioned 0 mm to 10 mm below the intra-commissural line, 2 mm to 14mm from midline, and 20 to about 40 mm anterior to the anteriorcommissure.
 3. The method of claim 1 wherein the depression is selectedfrom a group consisting of major depressive disorder and bipolardisorder.
 4. The method of claim 1 wherein stimulation of the neuraltissue modulates other targets in the limbic-cortical circuit.
 5. Themethod of claim 1 further comprising administering chemical stimulation.6. The method of claim 5 wherein the chemical stimulation comprisesadministration of excitatory neurotransmitter agonists.
 7. The method ofclaim 6 wherein the chemical stimulation comprises administration ofinhibitory neurotransmitter antagonists.